The rapid aging of the U.S. and populations in other industrialized and developing countries have led to a greater proportion of individuals at risk for Alzheimer's Disease (AD) a neurological, progressive, degenerative disease which is estimated to afflict 2 million Americans, and is one of the leading causes of death in the elderly population. Because of a possible "epidemic in dementia" and the large genetic component found in both early and late onset forms of AD, the NIMH awarded three centers at the University of Alabama at Birmingham (UAB), Harvard Medical School (HMS), and Johns Hopkins University (JHU), funds to collect 400 pairs of relatives, primarily sib-pairs. The overall objectives are to have as a national resource, a large enough sample of families which were obtained through implementation of a common protocol and consensus diagnostic procedures, for finding susceptibility genes linked to markers covering the majority of the human genome and for identifying clinical and genetic subtypes. Due to the recent advancements in the knowledge of genes involved in AD, the strong evidence for genetic heterogeneity in early and late onset AD and in order to provide sufficient and maximum power for identifying additional genes in light of this heterogeneity, the following specific aims are proposed: 1) Complete the collection of 133 families and the immortalization of their cell lines, and to add additional families for a total of 176 families. In doing so the goal of 533 cell lines per site will be reached, 2) Conduct longitudinal follow-up of all enrolled subjects, affected and unaffected, to document clinical progression, monitor any change in phenotype, obtain consents for autopsies, and obtain neuropathological data on affecteds and unaffecteds at risk to validate clinical diagnoses, provide data for subtyping of the disease and obtain information on the natural history of the disease process in gene carriers, and 3) Analyze the dataset for clinical and neuropathological correlates of specific genetic subtypes, distribution of subtypes of disease among families, onset patterns within sibships, and identification of possible risk and protective factors for onset of AD in susceptible family members. All the above will be accomplished by using the common protocol established for documenting the clinical and neuropathologic features of AD patients, and for operationalizing the Alzheimer's Disease Research Diagnostic Assessment (ADRDA/NINCDS) criteria for AD. The follow-up of family members to identify new onset AD will be accomplished using an instrument, validated in this population, and designed specifically to identify those mildly to moderately impaired. This national resource of 500 families should have sufficient power to identify additional genes for AD and identify genetic, clinical, and neuropathological subtypes of AD.